Preparation method for chlorinated compound

ABSTRACT

Disclosed is a method for preparing a chlorinated compound, and specifically disclosed is a method for preparing a compound represented by formula (I).

TECHNICAL FIELD

The present disclosure relates to a preparation method for a chlorinatedcompound, and in particular to a preparation method for a compound offormula (I).

BACKGROUND

In recent years, with the changes in people's living habits, the onsetof hyperuricemia and gout diseases has shown an upward trend year byyear. In Europe and America, epidemiological studies have shown that1-2% of the general population suffers from gouty arthritis, which isthe most common type of arthritis in adult males. Bloomberg estimatedthat there would be 17.7 million gout patients in 2021. In China, asurvey showed that 25.3% of the population aged 20 to 74 has a highblood uric acid level, and 0.36% suffers from gout diseases. At present,clinical therapeutic drugs mainly include: 1) drugs for inhibiting uricacid production, such as xanthine oxidase inhibitors allopurinol andfebuxostat; 2) uricosuric drugs, such as probenecid and benzbromarone;and 3) inflammation inhibitors, such as colchicine, and the like. Thesedrugs have certain defects in treatment, and poor efficacy, serious sideeffects and high cost are some of the main bottlenecks in their clinicalapplication. It has been reported that 40-70% of patients, afterreceiving standard treatment procedures, did not achieve the expectedtreatment goal (<6 mg/dL) in blood uric acid level.

URAT1 is an important kidney anion transporter located on the brushborder membrane of epithelial cells of renal tubules. It specificallytransports uric acid from renal tubules to epithelial cells and is themain driving force for the reabsorption of uric acid in renal tubules.Therefore, if the urate transporter URAT1 is significantly inhibited,the excretion of uric acid in the body can be increased, therebylowering the blood uric acid level and reducing the possibility of goutattacks.

In December 2015, AstraZeneca's Lesinurad, as shown below, was approvedby the U.S. FDA as the first URAT1-targeted inhibitor, and it at a doseof 200 mg/day was approved for use in combination with a xanthineoxidase inhibitor (XOI) (e.g., Febuxostat, etc.) for the treatment ofhyperuricemia and gouty arthritis. However, the additional effect of thecombined medication was not very significant as compared with thexanthine oxidase inhibitor alone. Meanwhile, Lesinurad at a dose of 400mg/day was not approved due to the significantly increased toxic sideeffects observed at high doses (higher incidence of kidney-relatedadverse events, especially kidney stone), although the combinedmedication demonstrated a higher additional effect at high doses.Accordingly, the FDA required the Lesinurad label to be filled with ablack box warning to warn the medical staff of the risk of acute renalfailure caused by Lesinurad, especially when it is not used incombination with XOI, and if an over-approved dose of Lesinurad is used,the risk of renal failure is even higher. Meanwhile, the FDA askedAstraZeneca to continue its investigation on kidney and cardiovascularsafety after the launch of Lesinurad. For long-term medication for ametabolic disease, the safety of the drugs is particularly important.Therefore, there is a strong demand in this field to develop a safe drugfor lowering blood uric acid level.

In the new drug declaration report disclosed by AstraZeneca, the resultsof the identification experiments of compound Lesinurad in livermicrosomes and hepatocyte metabolites of various animal species in vitrowere reported in detail. The data showed that M3 and M4, two mainmetabolites of Lesinurad, were significantly detected in the monkey andhuman hepatocytes, but M3 and M4 were not detected in dog and rathepatocytes, as shown in Table-a below.

TABLE a System Species M3 M4 Lesinurad Total Liver Rat — — 100 100microsome Dog — — 100 100 Monkey 7.9  — 92.1 100 Human — — 100 100Hepatocyte Rat — — 100 100 Dog — — 100 100 Monkey 1.45 0.47 98.1 100Human 2.24 5.69 92.1 100

Meanwhile, AstraZeneca also reported the main metabolites and metabolicpathways of Lesinurad after administration in various animal species,among which the dihydroxy metabolite M4 was specifically detected inhuman metabolites:

This was consistent with Lesinurad's clinical data in humans.Experimental data showed that M3 and M4 were the most predominantmetabolites found in human clinical trials, as shown in Table-b below.

TABLE b Time Percentage of administered dose System (h) M1 M2 M3 M3b M4M5 M5b M16 Other Lesinurad Total Urine 0-144 1.5 0.3 12.0 1.0 15.7 ND ND0.5 1.2 31.3 63.4 Feces 0-144 ND 4.8 0.3 1.9 5.0 3.6 7.8 1.1 7.5 1.533.5

According to the research, the production pathway of M4 metabolite couldbe determined as a result of the co-action of cytochrome CYP2C9 andprimate epoxide hydrolase mEH. This mEH metabolic pathway was unique toprimate species, which explained why no M4 was observed in rats anddogs.

CONTENT OF THE PRESENT INVENTION

The present disclosure provides a preparation method for a compound offormula (I),

which is characterized by comprising the following step:

wherein,

n is selected from 0, 1 and 2;

reagent A is selected from CS₂;

base B is selected from TEA, DBU, DIPEA and

and

solvent C is selected from a single solvent or a mixed solvent, whereinthe single solvent is selected from n-heptane, DMF, acetone and methyltert-butyl ether, and the mixed solvent is selected from a mixed solventof acetone and methyl tert-butyl ether.

In some embodiments of the present disclosure, provided is thepreparation method, wherein,

reagent A is selected from CS₂;

base B is selected from

and

solvent C is selected from a single solvent or a mixed solvent, whereinthe single solvent is selected from methyl tert-butyl ether, and themixed solvent is selected from a mixed solvent of acetone and methyltert-butyl ether.

In some embodiments of the present disclosure, provided is thepreparation method, wherein,

reagent A is selected from CS₂;

base B is selected from

and

solvent C is selected from a mixed solvent of acetone and methyltert-butyl ether.

In some embodiments of the present disclosure, provided is thepreparation method, wherein reagent A and compound 1-2 are in a molarratio of (1-6):1, base B and compound 1-2 are in a molar ratio of(2-5):1, and solvent C is a mixed solvent of methyl tert-butyl ether andacetone in a volume ratio of (15-25):1.

In some embodiments of the present disclosure, provided is thepreparation method, wherein a temperature of a reaction system iscontrolled at 0-45° C. in the step of preparing compound 1-3A.

In some embodiments of the present disclosure, provided is thepreparation method, wherein the temperature of the reaction system iscontrolled at 30-35° C. in the step of preparing compound 1-3A.

In some embodiments of the present disclosure, provided is thepreparation method, wherein a reaction time is controlled to be 16-60 hin the step of preparing compound 1-3A.

In some embodiments of the present disclosure, the preparation methodcomprises the following steps:

wherein,

reagent D is selected from hydrazine hydrate;

solvent E is selected from EtOH, isopropanol, toluene, MTBE, THF andDMF;

reagent F is selected from DMF-DMA; and

solvent G is selected from MTBE, EtOAc, n-heptane, THF, isopropanol andDMF.

In some embodiments of the present disclosure, provided is thepreparation method, wherein,

reagent D is selected from hydrazine hydrate;

solvent E is selected from EtOH and isopropanol;

reagent F is selected from DMF-DMA; and

solvent G is selected from isopropanol.

In some embodiments of the present disclosure, provided is thepreparation method, wherein reagent D and compound 1-3A are in a molarratio of (3-15):1, and reagent F and compound 1-4 are in a molar ratioof (1-3):1.

In some embodiments of the present disclosure, the preparation methodcomprises the following steps:

wherein,

n is selected from 0, 1 and 2;

reagent A, base B and solvent C are as defined above; and

reagent D, solvent E, reagent F and solvent G are as defined above.

In some embodiments of the present disclosure, the preparation methodcomprises the following steps:

wherein,

n is selected from 0, 1 and 2;

reagent A, base B and solvent C are as defined above;

reagent D, solvent E, reagent F and solvent G are as defined above;

base H is selected from a basic compound;

reagent I is selected from NCS;

solvent J is selected from EtOAc, DCM, PE, THF, MTBE and CH₃CN;

reagent K is selected from deacid reagent L is selected from K₂CO₃,NaHCO₃, K₃PO₄ and NaOAc;

solvent M is selected from EtOAc, DCM, DMF, THF and CH₃CN;

reagent N is selected from NBS and dibromohydantoin;

catalyst O is selected from thiocarbonyldiimidazole;

solvent P is selected from THF, CH₃CN and EtOAc;

reagent Q is selected from a base; and

solvent R is selected from a mixed solvent, wherein the mixed solvent isselected from a mixed solvent of tetrahydrofuran and water, a mixedsolvent of methanol and water, and a mixed solvent of methanol,tetrahydrofuran and water.

In some embodiments of the present disclosure, provided is thepreparation method, wherein,

reagent A, base B and solvent C are as defined above;

reagent D, solvent E, reagent F and solvent G are as defined above;

base H is selected from NaOH;

reagent I is selected from NCS;

solvent J is selected from EtOAc;

reagent K is selected from deacid reagent L is selected from NaOAc;

solvent M is selected from EtOAc;

reagent N is selected from NBS;

catalyst O is selected from thiocarbonyldiimidazole;

solvent P is selected from EtOAc;

reagent Q is selected from lithium hydroxide monohydrate, lithiumhydroxide, sodium hydroxide and potassium hydroxide; and

solvent R is selected from a mixed solvent of tetrahydrofuran and purewater in a volume ratio of (0.25-4):1.

The present disclosure provides a preparation method for a compound offormula (I),

which is characterized by comprising the following step:

wherein,

reagent A is selected from CS₂;

base B is selected from TEA, DBU, DIPEA and

and

solvent C is selected from a single solvent and a mixed solvent, whereinthe single solvent is selected from n-heptane, DMF, acetone and methyltert-butyl ether, and the mixed solvent is selected from a mixed solventof acetone and methyl tert-butyl ether.

In some embodiments of the present disclosure, provided is thepreparation method, wherein,

reagent A is selected from CS₂;

base B is selected from

and

solvent C is selected from a single solvent and a mixed solvent, whereinthe single solvent is selected from methyl tert-butyl ether, the mixedsolvent is selected from a mixed solvent of acetone and methyltert-butyl ether, and the other variables are as defined herein.

In some embodiments of the present disclosure, provided is thepreparation method, wherein,

reagent A is selected from CS₂;

base B is selected from

and

solvent C is selected from a mixed solvent of acetone and methyltert-butyl ether, and the other variables are as defined herein.

In some embodiments of the present disclosure, provided is thepreparation method, wherein reagent A and compound 1-2 are in a molarratio of (1-6):1, base B and compound 1-2 are in a molar ratio of(2-5):1, solvent C is a mixed solvent of methyl tert-butyl ether andacetone in a volume ratio of (15-25):1, and the other variables are asdefined herein.

In some embodiments of the present disclosure, provided is thepreparation method, wherein a temperature of a reaction system iscontrolled at 0-45° C. in the step of preparing compound 1-3A, and theother variables are as defined herein.

In some embodiments of the present disclosure, provided is thepreparation method, wherein the temperature of the reaction system iscontrolled at 30-35° C. in the step of preparing compound 1-3A, and theother variables are as defined herein.

In some embodiments of the present disclosure, provided is thepreparation method, wherein a reaction time is controlled to be 16-60 hin the step of preparing compound 1-3A, and the other variables are asdefined herein.

In some embodiments of the present disclosure, the preparation methodcomprises the following steps:

wherein,

reagent D is selected from hydrazine hydrate;

solvent E is selected from EtOH, isopropanol, toluene, MTBE, THF andDMF;

reagent F is selected from DMF-DMA; and

solvent G is selected from MTBE, EtOAc, n-heptane, THF, isopropanol andDMF, and the other variables are as defined herein.

In some embodiments of the present disclosure, provided is thepreparation method, wherein,

reagent D is selected from hydrazine hydrate;

solvent E is selected from EtOH and isopropanol;

reagent F is selected from DMF-DMA; and

solvent G is selected from isopropanol, and the other variables are asdefined herein.

In some embodiments of the present disclosure, provided is thepreparation method, wherein reagent D and compound 1-3A are in a molarratio of (3-15):1, reagent F and compound 1-4 are in a molar ratio of(1-3):1, and the other variables are as defined herein.

In some embodiments of the present disclosure, the preparation methodcomprises the following steps:

wherein,

reagent A, base B and solvent C are as defined herein; and

reagent D, solvent E, reagent F and solvent G are as defined herein, andthe other variables are as defined herein.

In some embodiments of the present disclosure, the preparation methodcomprises the following steps:

wherein,

reagent A, base B and solvent C are as defined herein;

reagent D, solvent E, reagent F and solvent G are as defined herein;

base H is selected from a basic compound;

reagent I is selected from NCS;

solvent J is selected from EtOAc, DCM, PE, THF, MTBE, and CH₃CN;

reagent K is selected from

deacid reagent L is selected from K₂CO₃, NaHCO₃, K₃PO₄ and NaOAc;

solvent M is selected from EtOAc, DCM, DMF, THF and CH₃CN;

reagent N is selected from NBS and dibromohydantoin;

catalyst O is selected from thiocarbonyldiimidazole;

solvent P is selected from THF, CH₃CN and EtOAc;

solvent Q is selected from a base; and

solvent R is selected from a mixed solvent, wherein the mixed solvent isselected from a mixed solvent of tetrahydrofuran and water, a mixedsolvent of methanol and water, and a mixed solvent of methanol,tetrahydrofuran and water, and the other variables are as definedherein.

In some embodiments of the present disclosure, provided is thepreparation method, wherein,

reagent A, base B and solvent C are as defined herein;

reagent D, solvent E, reagent F and solvent G are as defined herein;

base H is selected from NaOH;

reagent I is selected from NCS;

solvent J is selected from EtOAc;

reagent K is selected from

deacid reagent L is selected from NaOAc;

solvent M is selected from EtOAc;

reagent N is selected from NBS;

catalyst O is selected from thiocarbonyldiimidazole;

solvent P is selected from EtOAc;

solvent Q is selected from lithium hydroxide monohydrate; and

solvent R is selected from a mixed solvent of tetrahydrofuran and purewater, and the other variables are as defined herein.

The present disclosure provides a preparation method for a compound offormula (I),

which is characterized by comprising the following step:

wherein,

reagent A is selected from CS₂;

base B is selected from

and

solvent C is selected from a single solvent or a mixed solvent, whereinthe single solvent is selected from n-heptane, DMF, acetone and methyltert-butyl ether, and the mixed solvent is selected from a mixed solventof acetone and methyl tert-butyl ether.

In some embodiments of the present disclosure, provided is thepreparation method, wherein,

reagent A is selected from CS₂;

base B is selected from

and

solvent C is selected from a mixed solvent of acetone and methyltert-butyl ether, and the other variables are as defined herein.

In some embodiments of the present disclosure, provided is thepreparation method, wherein reagent A and compound 1-2 are in a molarratio of (1-6):1, base B and compound 1-2 are in a molar ratio of(2-5):1, solvent C is a mixed solvent of methyl tert-butyl ether andacetone in a volume ratio of (15-25):1, and the other variables are asdefined herein.

In some embodiments of the present disclosure, provided is thepreparation method, wherein a temperature of a reaction system iscontrolled at 0-45° C. in the step of preparing compound 1-3A, and theother variables are as defined herein.

In some embodiments of the present disclosure, provided is thepreparation method, wherein the temperature of the reaction system iscontrolled at 30-35° C. in the step of preparing compound 1-3A, and theother variables are as defined herein.

In some embodiments of the present disclosure, provided is thepreparation method, wherein a reaction time is controlled to be 16-60 hin the step of preparing compound 1-3A, and the other variables are asdefined herein.

In some embodiments of the present disclosure, the preparation methodcomprises the following steps:

wherein,

reagent D is selected from hydrazine hydrate;

solvent E is selected from EtOH, isopropanol, toluene, MTBE, THF andDMF;

reagent F is selected from DMF-DMA; and

solvent G is selected from MTBE, EtOAc, n-heptane, THF, isopropanol andDMF, and the other variables are as defined herein.

In some embodiments of the present disclosure, provided is thepreparation method, wherein,

reagent D is selected from hydrazine hydrate;

solvent E is selected from EtOH and isopropanol;

reagent F is selected from DMF-DMA; and

solvent G is selected from isopropanol, and the other variables are asdefined herein.

In some embodiments of the present disclosure, provided is thepreparation method, wherein reagent D and compound 1-3A are in a molarratio of (3-15):1, reagent F and compound 1-4 are in a molar ratio of(1-3):1, and the other variables are as defined herein.

In some embodiments of the present disclosure, the preparation methodcomprises the following steps:

wherein,

base B is selected from

reagent A and solvent C are as defined herein; and

reagent D, solvent E, reagent F and solvent G are as defined herein, andthe other variables are as defined herein.

In some embodiments of the present disclosure, the preparation methodcomprises the following steps:

wherein,

base B is selected from

reagent A and solvent C are as defined herein;

reagent D, solvent E, reagent F and solvent G are as defined herein;

base H is selected from a basic compound;

reagent I is selected from NCS;

solvent J is selected from EtOAc, DCM, PE, THF, MTBE and CH₃CN;

reagent K is selected from

deacid reagent L is selected from K₂CO₃, NaHCO₃, K₃PO₄ and NaOAc;

solvent M is selected from EtOAc, DCM, DMF, THF and CH₃CN;

reagent N is selected from NBS and dibromohydantoin;

catalyst O is selected from thiocarbonyldiimidazole;

solvent P is selected from THF, CH₃CN and EtOAc;

reagent Q is selected from a base; and

solvent R is selected from a mixed solvent, wherein the mixed solvent isselected from a mixed solvent of tetrahydrofuran and water, a mixedsolvent of methanol and water, and a mixed solvent of methanol,tetrahydrofuran and water, and the other variables are as definedherein.

In some embodiments of the present disclosure, provided is thepreparation method, wherein,

reagent A, base B and solvent C are as defined herein;

reagent D, solvent E, reagent F and solvent G are as defined herein;

base H is selected from NaOH;

reagent I is selected from NCS;

solvent J is selected from EtOAc;

reagent K is selected from

deacid reagent L is selected from NaOAc;

solvent M is selected from EtOAc;

reagent N is selected from NBS;

catalyst O is selected from thiocarbonyldiimidazole;

solvent P is selected from EtOAc;

reagent Q is selected from lithium hydroxide monohydrate, lithiumhydroxide, sodium hydroxide and potassium hydroxide; and

solvent R is selected from a mixed solvent of tetrahydrofuran and purewater in a volume ratio of (0.25-4):1, and the other variables are asdefined herein.

Technical Effects

The process for synthesizing the compound of formula (I) and theintermediates thereof provided herein has the following beneficialeffects: the raw materials are cheap and easy to obtain, and the defectssuch as difficulties in separation, purification and industrializationare overcome.

The details are as follows:

1) The raw materials used in the preparation method for the compound offormula (I) disclosed herein are conventional or common reagents, whichare easy to obtain in the market and low in price, and the use ofhigh-toxicity reagents is avoided;

2) The preparation of the compound features mild reaction conditions,ease-to-control, and simple post-treatment, a solid product is directlyprecipitated, and a product with higher purity can be obtained throughsimple recrystallization. The yield is high, and industrialization iseasy to realize.

Therefore, the present disclosure has high industrial application valueand economic value in the preparation of the compound of formula (I) andthe intermediates thereof.

Definitions and Description

Unless otherwise stated, the following terms and phrases used in thepresent disclosure are intended to have the following meanings. Aparticular term or phrase, unless otherwise specifically defined, shouldnot be considered as uncertain or unclear, but construed according toits common meaning. When referring to a trade name, it is intended torefer to its corresponding commercial product or its active ingredient.

The compound of the present disclosure may have a specific geometric orstereoisomeric form. All such compounds are contemplated herein,including cis and trans isomers, (−)- and (+)-enantiomers, (R)- and(S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and racemicmixtures and other mixtures thereof, such as an enantiomer ordiastereomer enriched mixture, all of which are encompassed within thescope of the present disclosure. Substituents such as alkyl may have anadditional asymmetric carbon atom. All these isomers and mixturesthereof are encompassed within the scope of the present disclosure.

Unless otherwise stated, the term “enantiomer” or “optical isomer”refers to stereoisomers that are mirror images of each other.

Unless otherwise stated, the term “cis-trans isomer” or “geometricisomer” results from the inability of a single bond of a ring carbonatom or a double bond to rotate freely.

Unless otherwise stated, the term “diastereoisomer” refers tostereoisomers in which molecules each have two or more chiral centersand are not mirror images of each other.

Unless otherwise stated, “(+)” stands for dextrorotation, “(−)” standsfor levorotation, and “(±)” stands for racemization.

Unless otherwise stated, the absolute configuration of a stereogeniccenter is represented by a wedged solid bond (

) and a wedged dashed bond (

), and the relative configuration of a stereogenic center is representedby a straight solid bond (

) and a straight dashed bond (

). A wavy line (

) represents a wedged solid bond (

) or a wedged dashed bond (

), or a wavy line (

) represents a straight solid bond (

) and a straight dashed bond (

).

Unless otherwise stated, when a double bond structure such as acarbon-carbon double bond, a carbon-nitrogen double bond, and anitrogen-nitrogen double bond is present in the compound, and each atomon the double bond is linked to two different substituents (in thedouble bond including a nitrogen atom, a lone pair of electrons on thenitrogen atom is regarded as a substituent to which the nitrogen atom islinked), if the atom on the double bond of the compound and itssubstituents are linked using a wavy line (

), it means that the compound exists in the form of a (Z)-type isomer,an (E)-type isomer, or a mixture of the two isomers. For example, thefollowing formula (A) represents that the compound exists in the form ofa single isomer of formula (A-1) or formula (A-2) or in the form of amixture of both isomers of formula (A-1) and formula (A-2); thefollowing formula (B) represents that the compound exists in the form ofa single isomer of formula (B-1) or formula (B-2) or in the form of amixture of both isomers of formula (B-1) and formula (B-2); and thefollowing formula (C) represents that the compound exists in the form ofa single isomer of formula (C-1) or formula (C-2) or in the form of amixture of both isomers of formula (C-1) and formula (C-2).

Unless otherwise stated, the term “isomeric excess” or “enantiomericexcess” refers to the difference between the relative percentages of twoisomers or enantiomers. For example, if the content of one isomer orenantiomer is 90% and the content of the other isomer or enantiomer is10%, the isomeric or enantiomeric excess (ee) is 80%.

The compound of the present disclosure may contain an unnaturalproportion of atomic isotope at one or more of the atoms that constitutethe compound. For example, the compound may be labeled with aradioisotope, such as tritium (³H), iodine-125 (¹²⁵1), or C-14 (¹⁴C).For another example, hydrogen can be substituted by deuterium to form adeuterated drug, and the bond formed by deuterium and carbon is firmerthan that formed by common hydrogen and carbon. Compared with anun-deuterated drug, the deuterated drug has the advantages of reducedtoxic side effect, increased stability, enhanced efficacy, and prolongedbiological half-life and the like. All isotopic variations of thecompounds of the present disclosure, whether radioactive or not, areencompassed within the scope of the present disclosure.

The intermediate compounds of the present disclosure can be prepared bya variety of synthetic methods well known to those skilled in the art,including the specific embodiments listed below, embodiments formed bycombinations thereof with other chemical synthetic methods, andequivalent substitutions thereof known to those skilled in the art.Preferred embodiments include, but are not limited to, the examples ofthe present disclosure.

The chemical reactions of the specific embodiments of the presentdisclosure are carried out in a suitable solvent that must be suitablefor the chemical changes in the present disclosure and the reagents andmaterials required. In order to obtain the compounds of the presentdisclosure, it is sometimes necessary for those skilled in the art tomodify or select a synthesis procedure or a reaction scheme based on theexisting embodiments.

The present disclosure is described in detail below by way of examples,which are not intended to limit the present disclosure in any way.

The solvents used in the present disclosure can be commerciallyavailable. The following abbreviations are used in the presentdisclosure:

DMF-DMA N,N-Dimethylformamide dimethyl acetal DCM Dichloromethane THFTetrahydrofuran DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide EtOHEthanol TEA Triethanolamine DBU 1,8-Diazabicycloundec-7-ene CS₂ Carbondisulfide DIPEA N,N-Diisopropylethylamine MTBE Methyl tert-butyl etherEtOAc Ethyl acetate CH₃CN Acetonitrile K₂CO₃ Potassium carbonate NaHCO₃Sodium bicarbonate K₃PO₄ Potassium phosphate NCS N-Chlorosuccinimide PEPetroleum ether NaOAc Sodium acetate NBS N-Bromosuccinimide

Compounds are named according to conventional nomenclature rules in theart or using ChemDraw® software, and supplier's catalog names are givenfor commercially available compounds.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

In order to better understand the content of the present disclosure,further description is given with reference to specific examples, butthe specific embodiments are not intended to limit the content of thepresent disclosure.

Example 1: Preparation of Compound of Formula (I)

Step 1: Synthesis of Compound 1-2

Compound 1-1 (1.0 kg, 4.55 mol, 1 eq) was added to 5.0 L of water, theresulting mixture was adjusted to pH of about 10 with a 2 M aqueous NaOHsolution, and then extracted with 5.0 L of ethyl acetate. The organicphases were dried over anhydrous sodium sulfate and filtered. The filtercake was washed with 2.0 L of ethyl acetate. The mother liquors werecombined and concentrated under reduced pressure to obtain a free 1-1.At an external temperature of 25-30° C., the free 1-1 was dissolved inethyl acetate (5.0 L), and then N-chlorosuccinimide (668.32 g, 5.01 mol,1.1 eq) was added in batches. After the addition was completed, theinternal temperature was raised to 40-45° C. The resulting reactionsolution was further stirred for 12 h. As the reaction proceeded, theinternal temperature slowly dropped to 25-30° C. The reaction solutionwas filtered through celite, and a mother liquor was collected. 7.0 L ofa 10% aqueous sodium bisulfite solution was added to the mother liquor,the resulting mixture was stirred for 15 min, and the liquids wereseparated. The organic phase was further washed twice with 7.0 L of a10% aqueous sodium bisulfite solution. The resulting organic phase wasthen washed once with water (7.0 L), washed once with a saturatedaqueous sodium chloride solution (7.0 L), dried over anhydrous sodiumsulfate (1 kg), and filtered. The filtrate was concentrated underreduced pressure to obtain compound 1-2 (896.36 g, 90.47% yield). ¹H NMR(400 MHz, CDCl₃) δ: 8.41-8.35 (m, 1H), 7.85-7.80 (m, 1H), 7.57-7.52 (m,2H), 7.19 (d, J=0.8 Hz, 1H), 4.43 (s, 2H), 2.26-2.17 (m, 1H), 1.07-0.97(m, 2H), 0.74-0.67 (m, 2H); MS m/z: 217.9 [M+H]⁺.

Step 2: Synthesis of Compound 1-3

Compound 1-2 (650.00 g, 2.98 mol, 1 eq) was dissolved in a mixed solventof methyl tert-butyl ether and acetone (6.5 L, V:V=95:5) at 25-30° C.,and then carbon disulfide (1134.49 g, 14.9 mol, 5 eq) and triethylenediamine (1002.79 g, 8.94 mol, 3 eq) were added sequentially withstirring. The resulting reaction solution was stirred at 30-35° C. for48 h. After the reaction was completed, the stirring was continued, andthe reaction solution was programmed-cooled to 0° C. (the cooling ratewas controlled at 5° C./h). The suspension was filtered, and the filtercake was washed twice with 100 mL of a mixed solvent of methyltert-butyl ether and acetone (methyl tert-butyl ether:acetone=95:5,v:v), and dried in vacuum to obtain compound 1-3 as a light yellow solid(1345.68 g, 90.51% yield). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.86 (br s, 1H),8.37-8.31 (m, 1H), 7.93-7.85 (m, 1H), 7.59-7.51 (m, 2H), 7.20 (s, 1H),3.82 (br s, 24H), 2.45-2.35 (m, 1H), 1.11-1.01 (m, 2H), 0.80-0.71 (m,2H).

Step 3: Synthesis of Compound 1-4

Compound 1-3 (530.0 g, 0.97 mol, 1 eq) and 3.5 L of ethanol (EtOH) wereadded to a reaction flask. The resulting mixture was stirred, andhydrazine hydrate (248.34 g, 4.86 mol, 5 eq) was added dropwise at20-23° C. After the dropwise addition was completed, the resulting mixedsolution was stirred at 20-23° C. for 18 h, followed by addition ofhydrazine hydrate (12 mL). The resulting reaction solution was furtherstirred at 20-23° C. for 48 h, and then filtered. The filter cake waswashed twice with 100 mL of ethanol. The washed filter cake wascollected and dried in a vacuum drying oven at 35° C. to obtain compound1-4 (271.82 g, 90.05% yield). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.22 (br s,1H), 8.48-8.31 (m, 1H), 7.91-7.75 (m, 1H), 7.67-7.48 (m, 2H), 7.27 (s,1H), 2.80 (s, 2H), 2.47-2.40 (m, 1H), 1.12-1.08 (m, 2H), 0.85-0.71 (m,2H); MS m/z: 291.9 [M+H]⁺.

Step 4: Synthesis of Compound 1-5

To a reaction flask were sequentially added 1-4 (260.0 g, 0.89 mol, 1eq), isopropanol (1.3 L) and N,N-dimethylformamide dimethyl acetal(159.26, 1.34 mol, 1.5 eq), and the resulting mixture solution wasstirred at 60° C. for 16 h. The reaction solution was concentrated underreduced pressure to about 500 mL, cooled to room temperature, andadjusted to pH=5-6 with a diluted aqueous hydrochloric acid solution (1M). The resulting reaction solution was further stirred for 2 h, andthen filtered. The filter cake was washed with 200 mL of filtered motherliquor. The washed filter cake was collected and dried in vacuum toobtain a light grey solid. The solid was stirred and slurried with 2.0 Lof n-heptane, and the resulting slurry was stirred at 20-25° C. for 16h, and filtered. The filter cake was washed twice with n-heptane (200mL). The washed filter cake was collected and dried under reducedpressure to obtain compound 1-5 (210.68 g, 83.35% yield). ¹H NMR (400MHZ, CD₃OD) δ: 8.58 (d, J=8.0 Hz, 1H), 8.37 (s, 1H), 7.73-7.67 (m, 1H),7.67-7.62 (m, 1H), 7.48-7.45 (m, 1H), 7.38-7.34 (m, 1H), 2.59-2.49 (m,1H), 1.25-1.18 (m, 2H), 0.96-0.84 (m, 2H); MS m/z: 301.9 [M+H]⁺.

Step 5: Synthesis of Compound 1-6

To a 5 L three-necked flask were sequentially added compound 1-5 (330.02g) and ethyl acetate (3.3 L), and the resulting mixture was stirredhomogeneously. Sodium acetate (179.68 g) was then added in one portion,and the resulting mixture was stirred homogeneously. Subsequently,methyl bromoacetate (200.86 g) was added in one portion, and theresulting mixture was stirred homogeneously. The resulting reactionsolution was stirred and reacted at an external temperature of 60° C.for 16 h, then filtered (at an external temperature of 60° C.) while itwas still hot. The filter cake was washed twice with ethyl acetate (100mL), and the filtrates were combined. Four batches (of the same mass)were fed in parallel by the same process, and the ethyl acetatefiltrates obtained by filtration after the reaction was completed werecombined and treated in the following manner.

Washing for the first time: 14 L of pure water was added to the aboveethyl acetate filtrate. The resulting mixture was vigorously stirred for20 min, and then left standing for separation. After the separation, theaqueous phase was discharged, and a small amount of flocculent layerremained in the ethyl acetate phase.

Washing for the second time: 14 L of pure water was then added to theethyl acetate phase. The resulting mixture was vigorously stirred for 20min, and then left standing for separation. After the separation, theaqueous phase was discharged, and a small amount of flocculent layerremained in the ethyl acetate phase.

Washing for the third time: 14 L of pure water was then added to theethyl acetate phase. The resulting mixture was vigorously stirred for 20min, and then left standing for separation. After the separation, thelower aqueous phase was discharged. The lower organic phase containing asmall amount of floccule was filtered through celite, combined with theremaining organic phase (about 14 L in total), dried over anhydroussodium sulfate (5 kg), and filtered. The filtrate was concentrated underreduced pressure to obtain a dark red oil, which was then left standingand cooled to room temperature to obtain a crude product of 1-6 as adark red solid (1640.73 g, 87.11% yield). ¹H NMR (400 MHz, DMSO-d₆) δ:8.94 (s, 1H), 8.58 (d, J=8.0 Hz, 1H), 7.84-7.66 (m, 2H), 7.52 (s, 1H),7.12 (d, J=8.0 Hz, 1H), 4.16-4.05 (m, 2H), 3.63 (s, 3H), 2.66-2.56 (m,1H), 1.23-1.11 (m, 2H), 1.01-0.83 (m, 2H); MS m/z: 374.0 [M+H]⁺.

Step 6: Synthesis of Compound 1-7

To a 5 L three-necked flask were sequentially added compound 1-6 (330.05g) and ethyl acetate (3.3 L). The resulting mixed solution was stirredat an external temperature of 40-45° C. until completely dissolved.Thiocarbonyldiimidazole (15.73 g) was added with stirring, and theresulting mixture was further stirred at an external temperature of40-45° C. for 10 min. N-Bromosuccinimide (157.10 g) was added in batcheswith stirring, and the resulting reaction solution was further stirredat an external temperature of 40-45° C. for 1 h. Finally,N-bromosuccinimide (15.74 g) was added, and the resulting reactionsolution was further stirred at an external temperature of 40-45° C. for15 min, then cooled to room temperature and filtered through celite. Thefilter cake was washed twice with ethyl acetate (200 mL), and thefiltrates were combined. Five batches (of the same mass) were fed inparallel by the same process, and the ethyl acetate filtrates obtainedby filtration after the reaction was completed were combined and thentreated in the following manner.

Washing for the first time: 17.2 L of pure water was added to the aboveethyl acetate filtrate. The resulting mixture was vigorously stirred for20 min, and then left standing for separation. After the separation, theaqueous phase was discharged, and a small amount of flocculent layerremained in the ethyl acetate phase.

Washing for the second time: 17.2 L of a 10% sodium bisulfite solutionwas then added to the ethyl acetate phase. The resulting mixture wasvigorously stirred for 20 min, and then left standing for separation.After the separation, the aqueous phase was discharged, and a smallamount of flocculent layer remained in the ethyl acetate phase.

Washing for the third time: 17.2 L of a 10% sodium bisulfite solutionwas then added to the ethyl acetate phase. The resulting mixture wasvigorously stirred for 20 min, and then left standing for separation.After the separation, the aqueous phase was discharged, and a smallamount of flocculent layer remained in the ethyl acetate phase.

Washing for the fourth time: 17.2 L of pure water was added to the aboveethyl acetate filtrate. The resulting mixture was vigorously stirred for20 min, and then left standing for separation. After the separation, theaqueous phase was discharged, and a small amount of flocculent layerremained in the ethyl acetate phase.

Washing for the fifth time: 17.2 L of pure water was added to the aboveethyl acetate filtrate. The resulting mixture was vigorously stirred for20 min, and then left standing for separation. After the separation, thelower aqueous phase was discharged. The lower organic phase containing asmall amount of floccule was filtered through celite, combined with theremaining organic phase (about 17 L in total), and dried over anhydroussodium sulfate (8 kg). The desiccant was removed by filtration, and thefiltrate was concentrated under reduced pressure to obtain a crudeproduct as a dark red solid (1562.17 g).

The above dark red solid was added to methyl tert-butyl ether (5.5 L),and the resulting mixture was stirred at an external temperature of 80°C. until it became clear. To the methyl tert-butyl ether solution wasfurther added n-heptane (3.5 L). The resulting mixed solution wasstirred at an external temperature of 60° C. for 16 h, and a largeamount of solid was then precipitated in the solution. Then n-heptane(2.0 L) was added. The resulting mixed solution was further stirred atan external temperature of 60° C. for 2 h, and then programmed-cooled toan external temperature of 40° C. (5° C./h). The stirring was stopped,and then filtration was performed. The filter cake was washed thoroughlywith n-heptane (1.5 L). The washed filter cake was collected and driedin vacuum at 40° C. for 2 h to obtain a light yellow solid (1107.09 g).

The above light yellow solid (1100.01 g) was added to isopropanol (5.5L), and the resulting mixture was heated to an external temperature of110° C. and refluxed to obtain a clear solution. The isopropanolsolution was programmed-cooled to an external temperature of 95° C. (5°C./h), and further stirred at this temperature for 16 h. A small amountof off-white solid was precipitated. The resulting mixture was furtherprogrammed-cooled to an external temperature of 60° C. (5° C./h), andfurther stirred at this temperature for 60 h. A large amount of solidwas precipitated. The resulting mixture was filtered while it was stillhot, and the filter cake was washed thoroughly with isopropanol (500mL). The washed filter cake was collected and dried in vacuum at 40° C.for 16 h to obtain 1-7 as a light yellow solid (962.69 g, 52.27% yield).¹H NMR (400 MHz, CD₃OD) δ: 8.63 (d, J=8.3 Hz, 1H), 7.82-7.65 (m, 2H),7.51 (s, 1H), 7.29-7.20 (m, 1H), 4.16-3.94 (m, 2H), 3.72 (s, 3H),2.64-2.49 (m, 1H), 1.30-1.20 (m, 2H), 0.99-0.85 (m, 2H); MS m/z: 453.7[M+H+2]⁺.

Step 7: Synthesis of Compound of Formula (I)

To a 5 L three-necked flask were sequentially added compound 1-7 (330.12g) and a mixed solution of anhydrous tetrahydrofuran (1650 mL) and purewater (1650 mL), and the resulting mixture was stirred homogeneously.Lithium hydroxide monohydrate (183.91 g) was then added in one portion,and the resulting reaction solution was stirred at an externaltemperature of 30° C. for 2 h. After the reaction was completed, thereaction solution was cooled to room temperature (20° C.). Three batcheswere fed in parallel by the same process. The reaction solutions werecombined and treated in the following manner.

The combined reaction solution was concentrated under reduced pressure(<40° C.) to remove tetrahydrofuran, and the aqueous phase was cooled to0° C. At 0° C., an aqueous hydrobromic acid solution (40%) was addeddropwise with stirring until the pH of the mixed solution was 3, and alarge amount of solid was precipitated. The mixture was further stirredat an external temperature of 20° C. for 16 h, and pH=3 wasredetermined. The mixture was filtered, and the filter cake was washedthoroughly with pure water (500 mL). The washed filter cake wascollected and dried in vacuum at 40° C. for 6 h to obtain a crudeproduct of the compound of formula (I) (895.65 g). To a 10 Lthree-necked flask were sequentially added the crude product of thecompound of formula (I) (890.12 g) and a mixed solution of ethanol (2225mL) and pure water (2225 mL), and the resulting mixture was stirred atan external temperature of 40° C. for 48 h, programmed-cooled to anexternal temperature of 20° C. (5° C./h), and then filtered. The filtercake was washed thoroughly with a mixed solution of ethanol and purewater (450 mL, V:V=1:1). The washed filter cake was collected and driedin vacuum at 40° C. for 16 h to obtain the compound of formula (I)(692.16 g, 77.78% yield). ¹H NMR (400 MHz, DMSO-d₆) δ: 13.02 (s, 1H),8.61 (d, J=8.4 Hz, 1H), 7.83-7.69 (m, 2H), 7.56 (d, J=8.0 Hz, 1H), 7.19(d, J=8.4 Hz, 1H), 4.12-3.96 (m, 2H), 2.69-2.57 (m, 1H), 1.24-1.13 (m,2H), 1.03-0.91 (m, 2H); MS m/z: 439.9 [M+H+2]⁺.

1. A preparation method for a compound of formula 1-3A, wherein, themethod comprises the following step:

wherein, n is selected from 0, 1 and 2; reagent A is selected from CS₂;base B is selected from TEA, DBU, DIPEA and

 and solvent C is selected from a single solvent or a mixed solvent,wherein the single solvent is selected from n-heptane, DMF, acetone andmethyl tert-butyl ether, and the mixed solvent is selected from a mixedsolvent of acetone and methyl tert-butyl ether.
 2. The preparationmethod according to claim 1, wherein reagent A is selected from CS₂;base B is selected from

 and solvent C is selected from a single solvent or a mixed solvent,wherein the single solvent is selected from methyl tert-butyl ether, andthe mixed solvent is selected from a mixed solvent of acetone and methyltert-butyl ether.
 3. The preparation method according to claim 2,wherein reagent A is selected from CS₂; base B is selected from

 and solvent C is selected from a mixed solvent of acetone and methyltert-butyl ether.
 4. The preparation method according to claim 1,wherein reagent A and compound 1-2 are in a molar ratio of (1-6):1, baseB and compound 1-2 are in a molar ratio of (2-5):1, and solvent C is amixed solvent of methyl tert-butyl ether and acetone in a volume ratioof (15-25):1.
 5. The preparation method according to claim 1, wherein atemperature of a reaction system is controlled at 0-45° C. in the stepof preparing compound 1-3A.
 6. The preparation method according to claim5, wherein the temperature of the reaction system is controlled at30-35° C. in the step of preparing compound 1-3A.
 7. The preparationmethod according to claim 1, wherein a reaction time is controlled to be16-60 h in the step of preparing compound 1-3A.
 8. A preparation methodfor a compound of formula 1-5, wherein the compound of formula 1-3A isprepared as in claim 1, and the preparation method comprises thefollowing steps:

wherein, reagent D is selected from hydrazine hydrate; solvent E isselected from EtOH, isopropanol, toluene, MTBE, THF and DMF; reagent Fis selected from DMF-DMA; and solvent G is selected from MTBE, EtOAc,n-heptane, THF, isopropanol and DMF.
 9. The preparation method accordingto claim 8, wherein reagent D is selected from hydrazine hydrate;solvent E is selected from EtOH and isopropanol; reagent F is selectedfrom DMF-DMA; and solvent G is selected from isopropanol.
 10. Thepreparation method according to claim 9, wherein reagent D and compound1-3A are in a molar ratio of (3-15):1, and reagent F and compound 1-4are in a molar ratio of (1-3):1.
 11. A preparation method for a compoundof formula (I), wherein the compound of formula 1-3A is prepared as inclaim 1, and the preparation method comprises the following steps:

wherein, n is selected from 0, 1 and 2; reagent D is selected fromhydrazine hydrate; solvent E is selected from EtOH and isopropanol;reagent F is selected from DMF-DMA; and solvent G is selected fromisopropanol.
 12. The preparation method according to claim 11,comprising the following steps:

wherein, n is selected from 0, 1 and 2; base H is selected from a basiccompound; reagent I is selected from NCS; solvent J is selected fromEtOAc, DCM, PE, THF, MTBE, and CH₃CN; reagent K is selected from

deacid reagent L is selected from K₂CO₃, NaHCO₃, K₃PO₄ and NaOAc;solvent M is selected from EtOAc, DCM, DMF, THF and CH₃CN; reagent N isselected from NBS and dibromohydantoin; catalyst O is selected fromthiocarbonyldiimidazole; solvent P is selected from THF, CH₃CN andEtOAc; reagent Q is selected from a base; and solvent R is selected froma mixed solvent, wherein the mixed solvent is selected from a mixedsolvent of tetrahydrofuran and water, a mixed solvent of methanol andwater, and a mixed solvent of methanol, tetrahydrofuran and water. 13.The preparation method according to claim 3 wherein reagent D isselected from hydrazine hydrate; solvent E is selected from EtOH andisopropanol; reagent F is selected from DMF-DMA; solvent G is selectedfrom isopropanol; base H is selected from NaOH; reagent I is selectedfrom NCS; solvent J is selected from EtOAc; reagent K is selected from

deacid reagent L is selected from NaOAc; solvent M is selected fromEtOAc; reagent N is selected from NBS; catalyst O is selected fromthiocarbonyldiimidazole; solvent P is selected from EtOAc; reagent Q isselected from lithium hydroxide monohydrate, lithium hydroxide, sodiumhydroxide and potassium hydroxide; and solvent R is selected from amixed solvent of tetrahydrofuran and pure water in a volume ratio of(0.25-4):1.